Leibniz and the ‘petites réflexions’

This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.In this article, I defend the thesis that Leibniz’s rational substances always have higher-order perceptions, even when they are, say, in a dreamless sleep. I argue that without this assumption, Leibniz’s conception of reflection would introduce discontinuities into his philosophy of mind which (given his Principle of Continuity) he cannot allow. This interpretation does not imply, however, that rational beings must be aware of these higher-order states at all times. In fact, these states are often unconscious or ‘small’ (analogous to Leibniz’s famous petites perceptions) and only count as reflections when they become distinct or heightened enough. Reflections thus arise out of ‘petites réflexions’ just as conscious perceptions arise out of petites perceptions. I argue, furthermore, that an analysis of some aspects of Leibniz’s theory of memory shows that he is not only committed to the thesis that rational beings always have higher-order states but that he also accepts it. I conclude by considering whether my interpretation is at odds with Leibniz’s doctrine of transcreation and also whether it has any consequences for which theory of consciousness we should ascribe to Leibniz.Peer Reviewe

Dynamics of trending topics between social media, news, and scientific literature

Information is disseminating more rapidly in today\u27s world than ever before in history. Every now and then, topics simultaneously gain massive attention in social media, dominate news headlines, and attract interest from researchers around the globe. While individual domains and networks are studied extensively, one question remains less addressed so far: How does information spread across different channels, considering dynamics between social media, news and, scientific literature? In this paper, we aim to identify frequent patterns in the dissemination of information over multiple channels. Based on an adapted pattern mining algorithm for multivariate time series, we provide strong indications for the existence of distinctive information diffusion effects between social media, news and scientific literature. We find that when all information channels simultaneously cover a certain topic, the preceding period is characterized either by a sole growth of social media coverage or a simultaneous growth of social media and news coverage

Molecular Characterization of mutated Histone H3.3 in childhood Glioblastoma

In recent years, affordable costs of next-generation sequencing technologies set the basis for the characterization of a multitude of cancer genomes. In doing so, scientists all over the world reconfirmed that cancer is a disease of the (epi)genome. The growing number of genetic abnormalities found in chromatin remodeling factors in various cancer entities produced evidence that aberrant chromatin modification plays an essential role in cancer initiation and progression. Besides numerous mutations of histone modifying factors in different cancer types, two recurrent mutations within the histone H3.3 coding gene H3F3A have been identified in about 50% of pediatric glioblastoma. Both mutations result in amino acid substitutions at two critical residues of the histone tail of H3.3 (K27M or G34R/V). Since glioblastomas harboring one of these H3.3 mutations are characterized by a complex but stereotypic pattern of genetic and epigenetic alterations, the project presented here uses a variety of molecular techniques to study the functional mechanisms associated with both H3.3 mutations. By using confocal imaging of fluorescently labeled H3.3 mutants and genome-wide sequencing-based chromatin immunoprecipitation (ChIP-Seq) of ectopically expressed H3.3 mutants, it was demonstrated that deposition and incorporation of histone H3.3 into chromatin is not affected by the mutations. Furthermore, experiments with different cell lines, which were genetically modified to stably overexpress mutant H3.3, provide evidence that (at least) some of the genome-wide changes that were originally found in H3.3 mutated glioblastomas, can be faithfully recapitulated in vitro. The investigation of several epigenetic marks by Western blot analysis and immunohistochemistry identified a strong dominant negative effect of the K27M mutant H3.3 protein, which causes global reduction of the key epigenetic mark H3K27me3. Moreover, this epigenetic alteration found in primary tumors, was induced in vitro by overexpression of K27M mutant H3.3 in different cell lines. By using mass spectrometry to dissect the pattern of posttranslational modifications (PTM) at the histone tail of G34R mutant H3.3, a new PTM has been identified, namely dimethylation of arginine 34. Furthermore, first evidence is provided that this new PTM is causative for the downregulation of K36 trimethylation at G34R mutant H3.3. Finally, overexpression of mutant H3.3 in the brain of neonatal mice was performed by retroviral gene transfer. In doing so, this study aims at the elucidation of the in vivo tumorigenic potential of both histone H3.3 mutations alone or in combination with impaired TP53 function. In summary, the findings of this thesis provide novel insights into the comprehensive epigenetic changes caused by mutant histone H3.3 in pediatric GBMs. These results might provide the basis for the development of novel therapeutic strategies targeting the epigenetic changes induced by H3.3 mutations, which have been identified recently in nearly half of the tumors in children suffering from this devastating brain tumor

Model-Based Edge Detector for Spectral Imagery Using Sparse Spatiospectral Masks

Two model-based algorithms for edge detection in spectral imagery are developed that specifically target capturing intrinsic features such as isoluminant edges that are characterized by a jump in color but not in intensity. Given prior knowledge of the classes of reflectance or emittance spectra associated with candidate objects in a scene, a small set of spectral-band ratios, which most profoundly identify the edge between each pair of materials, are selected to define a edge signature. The bands that form the edge signature are fed into a spatial mask, producing a sparse joint spatiospectral nonlinear operator. The first algorithm achieves edge detection for every material pair by matching the response of the operator at every pixel with the edge signature for the pair of materials. The second algorithm is a classifier-enhanced extension of the first algorithm that adaptively accentuates distinctive features before applying the spatiospectral operator. Both algorithms are extensively verified using spectral imagery from the airborne hyperspectral imager and from a dots-in-a-well midinfrared imager. In both cases, the multicolor gradient (MCG) and the hyperspectral/spatial detection of edges (HySPADE) edge detectors are used as a benchmark for comparison. The results demonstrate that the proposed algorithms outperform the MCG and HySPADE edge detectors in accuracy, especially when isoluminant edges are present. By requiring only a few bands as input to the spatiospectral operator, the algorithms enable significant levels of data compression in band selection. In the presented examples, the required operations per pixel are reduced by a factor of 71 with respect to those required by the MCG edge detector

Pharmakologische Modulation des Ca2+-Leckstroms aus dem Endoplasmatischen Retikulum mittels chemischer Chaperone

In all eukaryotic cells, the endoplasmic reticulum (ER) functions as a major site of protein synthesis and as main releasable Ca2+ storage organelle. Thus, ER is crucial for the cellular Ca2+-homeostasis in which the Sec61 complex, located in the ER membrane, serves as a protein translocase while also acting as Ca2+ leak channel allowing Ca2+ ions permeate into the cytosol. This aforementioned effect is referred to as Ca2+ efflux which is known to utilize regulatory Proteins available in the cytosol and ER Lumen including, but not limited to the ER luminal protein termed BiP. BiP belongs to the protein folding group named Chaperones which assist in protein folding and also suppresses Ca2+ leak from the ER. Furthermore, ER stress may cause Ca2+ leak from the ER into the cytosol altering cellular Ca2+ homeostasis to the point of apoptosis. Among other mechanisms, chemically produced chaperones, which induce protein folding, have also been shown to protect cells from ER stress. However, to this date studies are insufficient in identifying possible direct effects of chemical chaperones on cellular Ca2+ homeostasis and Ca2+ leak. This scientific research aims to explore and characterize comparatively and functionally the Ca2+ leak by using known Sec61 modulators independently, as well as in combination with two chemical chaperones known as 4-phenylbutyrate (4-PBA) and azoramide (AZO). For this purpose, Ca2+ imaging experiments using the cytosolic Ca2+ indicator Fura-2 were performed on human HEK-293 cells and their cellular Ca2+ homeostasis. A 12-minute treatment with aformentioned pharmacological agents 4-PBA or AZO resulted in a reduction of Ca2+ leak up to ~75%. Also, after pharmacological induced ER stress, treatment with the two chemical chaperones resulted in a significant reduction of Ca2+ leak also up to ~75% compared against the control group. In addition, a dose-dependent effect could be highlighted for 4-PBA and AZO, whereas prolongation of treatment with 4-PBA to 30 minutes resulted in a smaller reduction of Ca2+ efflux. The active metabolite phenyl acetate (PAA) decreased cytosolic Ca2+ leak by more than ~50%. Furthermore, incubation with 4-PBA was shown to result in a ~50% reduction in total cellular Ca2+ content. In conclusion these results indicate that chemical chaperones may have a protective effect on ER-stressed cells and positively influence Ca2+ homeostasis and/or Ca2+ leak.In allen eukaryotischen Zellen fungiert das Endoplasmatische Retikulum (ER) als Zellorganell der Proteinsynthese und als Hauptspeicherorganell für Ca2+ und ist somit entscheidend für die Ca2+-Homöostase der Zelle. Der in der ER-Membran befindliche Sec61-Komplex dient hierzu als Proteintranslokase und wurde zudem als ein Ca2+-Leckkanal beschrieben, durch den Ca2+-Ionen in das Zytosol permiieren. Zur Regulation dieses Ca2+-Efflux stehen im Zytosol und ER-Lumen Proteine zur Verfügung, zu denen auch das im ER befindliche BiP gehört. BiP zählt zu der Gruppe von Faltungshilfsprotein, die sog. Chaperone, und unterdrückt darüber hinaus das Ca2+-Leck aus dem ER. ER-Stress führt zu einem ungewollten Ca2+-Leck aus dem ER in das Zytosol, was die Ca2+-Homöostase der Zelle bis hin zur Apoptose verändert. Es hat sich gezeigt, dass chemisch hergestellte Chaperone unter anderem auch über dem Mechanismus der Proteinfaltung Zellen vor ER-Stress schützen können. Bisher ist jedoch der direkte Effekt von chemischen Chaperonen auf die Ca2+-Homöostase und das Ca2+-Leck von Zellen unzureichend untersucht worden. Ziel dieser Arbeit war es das Ca2+-Leck durch Verwendung von bekannten Sec61-Modulatoren gesondert, sowie in Kombination mit zwei chemischen Chaperone 4-Phenylbutyrat (4-PBA) und Azoramide (AZO) vergleichend und funktionell zu erforschen. Hierzu wurden Ca2+-Imaging-Experimente mittels des zytosolischen Ca2+-Indikators Fura-2 an humanen HEK-293 Zellen durchgeführt und die Ca2+-Homöostase dieser Zellen sowie deren Änderungen nach Behandlung mit obengenannten pharmakologischen Stoffen charakterisiert. Es konnte gezeigt werden, dass eine 12-minütige Behandlung mit 4-PBA oder AZO zu einer Reduktion des Ca2+-Lecks bis hin zu ~75% führte. Auch nach pharmakologische induzierte ER-Stress führte die Behandlung mit den beiden chemischen Chaperonen zu einer deutlichen Reduktion des Ca2+-Lecks ebenfalls bis hin zu ~75% im Vergleich zur Kontrollgruppe. Zusätzlich ließ sich ein dosisabhängiger Effekt für 4-PBA und AZO herausstellen, wohingegen die Verlängerung der Behandlung mit 4-PBA auf 30 Minuten in einer geringeren Senkung des Ca2+-Efflux resultierte. Der aktive Metabolit Phenylacetat (PAA) verringerte das zytosolische Ca2+-Leck um mehr als ~50%. Ferner zeigte sich, dass die Inkubation mit 4-PBA zu einer Verringerung des gesamten zellulären Ca2+-Gehaltes um ~50% führte. Diese Ergebnisse legen den Verdacht nahe, das chemische Chaperone möglicherweise einen protektiven Effekt auf unter ER-Stress stehende Zellen aufweisen und die Ca2+-Homöostase bzw. das Ca2+-Leck positiv beeinflussen

Probing atom-surface interactions by diffraction of Bose-Einstein condensates

In this article we analyze the Casimir-Polder interaction of atoms with a solid grating and an additional repulsive interaction between the atoms and the grating in the presence of an external laser source. The combined potential landscape above the solid body is probed locally by diffraction of Bose-Einstein condensates. Measured diffraction efficiencies reveal information about the shape of the Casimir-Polder interaction and allow us to discern between models based on a pairwise-summation (Hamaker) approach and Lifshitz theory.Comment: 5 pages, 4 figure

Ghost Busting: PT-Symmetric Interpretation of the Lee Model

The Lee model was introduced in the 1950s as an elementary quantum field theory in which mass, wave function, and charge renormalization could be carried out exactly. In early studies of this model it was found that there is a critical value of g^2, the square of the renormalized coupling constant, above which g_0^2, the square of the unrenormalized coupling constant, is negative. Thus, for g^2 larger than this critical value, the Hamiltonian of the Lee model becomes non-Hermitian. It was also discovered that in this non-Hermitian regime a new state appears whose norm is negative. This state is called a ghost state. It has always been assumed that in this ghost regime the Lee model is an unacceptable quantum theory because unitarity appears to be violated. However, in this regime while the Hamiltonian is not Hermitian, it does possess PT symmetry. It has recently been discovered that a non-Hermitian Hamiltonian having PT symmetry may define a quantum theory that is unitary. The proof of unitarity requires the construction of a new time-independent operator called C. In terms of C one can define a new inner product with respect to which the norms of the states in the Hilbert space are positive. Furthermore, it has been shown that time evolution in such a theory is unitary. In this paper the C operator for the Lee model in the ghost regime is constructed exactly in the V/N-theta sector. It is then shown that the ghost state has a positive norm and that the Lee model is an acceptable unitary quantum field theory for all values of g^2.Comment: 20 pages, 9 figure